The most common primary malignant brain tumor, glioblastoma multiforme (GBM), remains uniformly fatal despite surgical resection, radiation therapy, and chemotherapyl. Immunotherapy promises to induce robust, tumor-specific immune responses that eliminate neoplastic cells with unparalleled specificity without adding additional toxicity to multimodality therapy. Substantial evidence supports the role of T-cells in the eradication of cancer. Recently, the concept of using specific antibodies to re-direct T-cells has been optimized in the form of recombinant bispecific T-cell engaging molecules, or bispecific T-cell engaging molecules, that consist of a tumor-targeting single-chain antibody connected to a single-chain antibody directed against a Tcell activation ligand such as CD3. These bispecific T cell engaging molecules can tether T-cells to tumor cells, which results in a highly localized and specific activation of T-cells with concomitant tumor cell lysis. Recently, human trials using a CD19×CD3 bispecific T cell engaging molecule confirmed the potency of these constructs by tumor regression observed in 7/7 patients with non-Hodgkin's lymphoma at a dose of only 0.06 mg/m2 with clearance of tumor from the blood, bone marrow, and liver4. The most significant limitation of these promising constructs, however, is the lack of tumor-specific targets that are frequently and homogeneously expressed.
Tumor-specific antigens derived from mutations in somatic genes are less likely to be associated with autoimmunity, but often arise randomly as a result of the genetic instability of tumors and, as such, tend to be patient-specific and incidental to the oncogenic process. EGFRvIII, however, is a frequent and consistent tumor specific mutation, central to the neoplastic process, which consists of an in-frame deletion of 801 base pairs from the extracellular domain (ECD) of the EGFR that splits a codon and produces a novel glycine at the fusion junction. This mutation encodes a constitutively active tyrosine kinase that enhances neoplastic cell growth and migration9 and confers radiation and chemotherapeutic resistance to tumor cells. The EGFRvIII mutation is most frequently seen in patients with GBM, but has been found in a broad array of other common cancers. The new glycine inserted at the fusion junction of normally distant parts of the ECD results in a tumor-specific epitope that is not found in any normal tissues.
There is a continuing need in the art to find better and more successful treatments of cancers such as brain cancers.